Transforming growth factor (TGF-beta) is a multi-functional factor that induces a wide variety of cellular processes affecting growth and differentiation. In normal epithelial cells, including intestinal epithelium, TGF-beta has a potent growth inhibitory effect and serves a tumor suppressor role. On the other hand, under selected conditions TGF-beta may actually promote tumorigenesis. Mutations in the TGF-beta receptors and selected TGF-beta signal transduction proteins (Smad family of proteins) have been associated with a significant fraction of human colorectal and pancreatic cancers. Evidence suggests that several effects of TGF-beta such as increased chemotactic activity and invasiveness, increased expression of COX-2 and prostaglandin release and increased expression of RhoB cause a epithelial to mesenchymal expression of COX-2 and prostaglandin release and increased expression of RhoB cause a epithelial to mesenchymal transition (EMT). Based on recent observations, the central hypothesis of this proposal is: tumor promoting effects of TGF-beta over-ride tumor suppressor effects during of intestinal and other types of epithelial cells, due to a witch in TGF-beta signal transduction. A long term of this investigation is to identify novel therapeutic strategies that selectively target the tumor promoting effects of TGF-beta, while preserving the tumor suppressive actions.